Age-related defects in hematopoietic stem cell (HSC) function may hamper the application of HSC-based therapies for elderly individuals. We have undertaken a series of studies investigating HSC function in aged mice. With this model system, we have determined that aging leads to markedly inefficient generation of early B lymphocyte progenitor cells from HSCs. We propose to further explore the cellular and molecular basis for this defect via four specific aims. In Aim 1, we will determine when early B-lineage precursors first decline with age and define the earliest stage in B-lineage differentiation affected by the aging process. In Aim 2, we will test whether age-associated loss of early lymphoid progenitors is due to cell intrinsic defects in HSCs, and test whether noncanonical lymphoid progenitors contribute to the B cell lineage in the elderly. In Aim 3, we will elucidate the impact of HSC aging on the capacity of early B cell precursors to respond to the cytokine IL-7 and sustain B-lineage differentiation. Finally, in Aim 4, we will define the role of the E2a and EBF transcription factors in the age-associated loss of very early B-lineage progenitors. Together, these studies will enhance our knowledge of stem cell biology and the basis for age-related defects in early lymphocyte development.